Interventions for obsessive compulsive symptoms in people with schizophrenia

Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

1. Primary objectives

To evaluate clinically meaningful benefits of interventions used to treat clinically significant obsessive compulsive symptoms occurring in people with schizophrenia with regard to global improvement, changes in mental state, hospitalisation, behaviour and functioning in the short term (less than six weeks), medium term (six weeks to six months) and long term (more than six months).

In this review we specifically addressed the efficacy and safety of the following when used to treat clinically significant obsessive compulsive symptoms occurring in people with schizophrenia:

1.1 Conventional and newer (or atypical) antipsychotic drugs

1.2 Conventional and newer antidepressant drugs

1.3 Any other drug or pharmacologically active substance

1.4 Non-pharmacological interventions

In future versions of this review we will cover the use of psychosurgery, deep brain stimulation or other invasive interventions for this purpose.

2. Secondary objectives

To determine whether these interventions would have a differential effect:

2.1 In people with schizophrenia in whom obsessive compulsive symptoms preceded the onset of symptoms of schizophrenia as opposed to those in whom obsessive compulsive symptoms occurred in the prodromal stages or after the symptoms of schizophrenia were firmly established

2.2 In people with obsessive compulsive symptoms as opposed to obsessive compulsive disorder as defined by diagnostic criteria

BACKGROUND

Surveys conducted amongst people with schizophrenia show an estimated prevalence of co-morbid obsessive compulsive symptoms ranging from 8% to 46% (Craig 2002, Fenton 1986, Poyurovsky 1999, Poyurovsky 2001, Tibbo 2000). Approximately 15% to 30% meet diagnostic criteria for obsessive compulsive disorder (OCD) (Bermanzohn 2000, de Hann 2002a, Nechmad 2003). These rates are considerably higher than the 1.2 to 2.5% prevalence of obsessive compulsive disorder seen in the general population worldwide (Weissman 1994). Both OCD and schizophrenia often have their onset in adolescence, and both disorders often follow an episodic or chronic course, with considerable accompanying distress and disability (Steketee 1997). Obsessive compulsive symptoms may precede the onset of schizophrenia, occur in the prodromal phase, or appear during the course of the illness. The use of atypical antipsychotics has been associated with the emergence or worsening of obsessive compulsive symptoms; the drugs implicated in case series include clozapine (de Haan 1999, Robert 1992), olanzapine (Lykouras 2000), risperidone (Alevizos 2002) and quetiapine (Khullar 2001). However, prospective systematic surveys have not confirmed the propensity of risperidone or olanzapine to induce or exacerbate obsessive compulsive symptoms (Baker 1996, de Hann 2002a).

People with schizophrenia and co-morbid obsessive compulsive symptoms are generally characterised by: lower levels of social functioning, longer duration of hospitalisation, more neurocognitive impairment, greater severity of negative symptoms, greater propensity to develop extrapyramidal effects and treatment resistance than those without obsessive compulsive symptoms. (Fenton 1986, Eisen 1997, Hwang 2000, Kruger 2000, Poyurovsky 2001, Lysaker 2000, Lysaker 2002, Ohta 2003).

Obsessive compulsive disorder is commonly treated by antidepressant drugs, the talking therapies, sometimes antipsychotics and very rarely, psychosurgery, using stereotaxic techniques (Lopez 2004), or the more recent technique of deep brain stimulation (Nuttin 2003), also has reported benefits. Uncontrolled reports of the benefits of the antidepressant clomipramine and SSRI class of antidepressants in treating people with schizophrenia and co-morbid OCD are encouraging (Berman 1995, Khan 2004). However, atypical antipsychotics, though sometimes implicated in the emergence or worsening of obsessive compulsive symptoms, have also been effectively used to reduce these symptoms when used as the sole treatment (Poyurovsky 2000, Veznedaroglu 2003, Kumar 2003, Reznik 2004), or when used in conjunction with serotonergic drugs (Strous 1999, Reznik 2000, Poyurovsky 2003). Both SS-RIs (Poyurovsky 1996) and behavioural therapy (MacCabe 2002) have been used to effectively treat obsessive compulsive symptoms occurring after treatment with atypical antipsychotics.

The treatment strategy for those with schizophrenia who also experience obsessive compulsive symptoms or OCD remains unclear, and in this review we have attempted to answer the following questions. Would conventional or atypical antipsychotics be effective in treating those in whom these symptoms occur after the symptoms of schizophrenia have been established? Would these drugs be effective in those whose obsessive compulsive symptoms preceded the onset of schizophrenia? Would the dose of these drugs matter in treating obsessive compulsive symptoms, or would there be differences in the efficacy of conventional versus atypical drugs or between drugs from the same class? Would a combination of antipsychotic drugs and interventions that are effective in primary OCD be effective in those with schizophrenia and OCD? What would be the effect of these interventions on the core positive (delusions, hallucinations and disturbances in thinking) and negative (poor motivation, poor communication, poor socialisation and poor emotional response) symptoms of schizophrenia? Would they be equally effective late as opposed to early on in the course of schizophrenia?

Technical background

Neuro-imaging studies have revealed many common as well as dissimilar areas of structural changes in the brains of people with schizophrenia with and without OCD, and those with OCD compared to normal controls, chiefly involving the hippocampus; basal ganglia, in particular the caudate nucleus; the orbitofrontal cortex; the anterior cingulate gyrus and the medio-dorsal thalamic nucleus (Aoyama 2000, Gross-Isseroff 2003, Kim 2003, Kurokawa 2000, Kwon 2003). These common abnormalities, detected even early in the course of the disorder, and the overlap in the clinical presentations of these conditions, suggest a common neuro-developmental origin for these conditions and provide the basis for the suggestion that people with schizophrenia and co-morbid OCD may have a distinct subtype of schizophrenia that some have called ‘schizo-obsessive disorder’ or ‘obsessive-compulsive schizophrenia’. It is also possible that even among people with schizophrenia and comorbid OCD, there are subgroups defined by time of onset of schizophrenia in the course of the disorder and by other clinical or biological parameters (Lysaker 2004).

Obsessive compulsive disorder is commonly treated by drugs that act selectively or primarily on the neuro-transmitter called serotonin. Clomipramine and the selective serotonin reuptake inhibitors (SSRIs), such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline, are the first line treatments for people with OCD and are thought to be superior to anti-depressant drugs with no serotonergic properties (Piccinelli 1995). However, 40-60% of patients with obsessive compulsive disorder do not respond to adequate treatment with SSRIs or clomipramine (Kaplan 2003), and agents that alter serotonin receptors and other neurotransmitter systems, such as dopamine, norepinephrine, and second-messenger systems, may also play a role in treatment. More commonly, non-pharmacological methods such as behaviour therapy (BT) and cognitive behaviour therapy (CBT) are used, either alone or in conjunction with clomipramine or SSRIs. Behaviourtherapy is a specific technique where the person is exposed to stimuli that provoke obsessive thoughts but is prevented from making the compulsive response (exposure and response prevention or ERP) (Abramowitz 1997, Kobak 1998, McLean 2001). For those failing to show adequate response to any of these interventions, psychosurgery (Lopez 2004), or deep brain stimulation (Nuttin 2003), also has reported benefits.

OBJECTIVES

1. Primary objectives

To evaluate clinically meaningful benefits of interventions used to treat clinically significant obsessive compulsive symptoms occurring in people with schizophrenia with regard to global improvement, changes in mental state, hospitalisation, behaviour and functioning in the short term (less than six weeks), medium term (six weeks to six months) and long term (more than six months).

In this review we specifically addressed the efficacy and safety of the following when used to treat clinically significant obsessive compulsive symptoms occurring in people with schizophrenia:

1.1 Conventional and newer (or atypical) antipsychotic drugs

1.2 Conventional and newer antidepressant drugs

1.3 Any other drug or pharmacologically active substance

1.4 Non-pharmacological interventions

In future versions of this review we will cover the use of psychosurgery, deep brain stimulation or other invasive interventions for this purpose.

2. Secondary objectives

To determine whether these interventions would have a differential effect:

2.1 In people with schizophrenia in whom obsessive compulsive symptoms preceded the onset of symptoms of schizophrenia as opposed to those in whom obsessive compulsive symptoms occurred in the prodromal stages or after the symptoms of schizophrenia were firmly established

2.2 In people with obsessive compulsive symptoms as opposed to obsessive compulsive disorder as defined by diagnostic criteria

METHODS

Criteria for considering studies for this review

Types of studies

We included all relevant randomised controlled trials. Where a trial was described as ‘double-blind’, but it was only implied that the study was randomised, we included these trials in a sensitivity analysis. If there was no substantive difference within primary outcomes (see types of outcome measures) when these ‘implied randomisation’ studies were added, then we included these in the final analysis. If there was a substantive difference, we used only those trials that were clearly randomised and described the results of the sensitivity analysis in the text. We excluded quasi-randomised studies, such as those allocating by using alternate days of the week.

Types of participants

We included people with schizophrenia of all ages, diagnosed by any criteria, who also show obsessive compulsive symptoms, however diagnosed.

Types of interventions

1.1 Antipsychotic drugs: conventional or atypical

1.2 Antidepressant drugs: tricyclics, specific serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, mono-amine-oxidase inhibitors, other antidepressants.

1.3 Any other drug or pharmacologically active substance

1.4 Placebo

1.5 Behaviour therapy

1.6 Cognitive behaviour therapy

1.7 Other non-pharmacological interventions

It is expected that everyone in the studies would also be receiving antipsychotic medication with or without an anticholinergic drug for extrapyramidal symptoms.

Types of outcome measures

Primary outcomes

1. No clinical response

1.1 No clinically significant response in global state - as defined by each of the studies

1.2 No clinically significant response on psychotic symptoms - as defined by each of the studies

1.3 No clinically significant response on obsessive compulsive symptoms - as defined by each of the studies

2. Adverse effects, general and specific

Secondary outcomes

1. Death - suicide or natural causes

2. Leaving the study early or dropouts

3. No clinical response

3.1 Average score/change in global state

3.2 Average score/change on psychotic symptoms

3.3 Average score/change in obsessive compulsive symptoms

4. Extrapyramidal side effects

4.1 Use of anticholinergic drugs

4.2 No clinically significant extrapyramidal side effects - as defined by each of the studies

4.3 Average score/change in extrapyramidal side effects

6. Service utilisation outcomes

6.1 Hospital admission

6.2 Days in hospital

7. Economic outcomes

8. Quality of life / satisfaction with care for either recipients of care or carers

8.1 No significant change in quality of life / satisfaction - as defined by each of the studies

8.2 Average score / change in quality of life / satisfaction

Search methods for identification of studies

Electronic searches

We searched the Cochrane Schizophrenia Group’s Trials Register (December 2004) using the phrase:

[((*obsessi* or *compulsi* or *YBOCS* or *Y-BOCS*) in title, abstract and index terms in REFERENCE) and ((*obsessi* or *compulsi*) in outcomes in STUDY)]

This register is compiled by systematic searches of major databases, hand searches and conference proceedings (see Group Module). No language restrictions will be used for electronic searches.

Searching other resources

1. Citation searching

We inspected the citation lists from all identified studies for additional studies.

2. Personal contact

We contacted the first author of each included study published during the last ten years for additional references and for any unpublished trials.

3. Pharmaceutical companies

We contacted companies involved in the production of the principal antipsychotic, antidepressant and anti-obsessional drugs and requested additional studies.

4. Citations

We sought all selected studies as citations on the ISI database in order to identify more trials.

Data collection and analysis

1. Selection of trials

Two reviewers (RM, SF) independently inspected the citations identified from the search. Potentially relevant abstracts were identified and full papers ordered and reassessed for inclusion and methodological quality. Any disagreement during this process was discussed and reported.

2. Assessment of methodological quality

Trials were allocated to three quality categories, as described in the Cochrane Collaboration Handbook (Clarke 2001) by each reviewer, again, working independently. When disputes arose as to which category a trial was allocated to, resolution was attempted by discussion. When this was not possible, and further information was necessary, data were not entered into the analyses and the study was allocated to the list of those awaiting assessment. Only trials in Category A or B were included in the review.

3. Data management

3.1 Data extraction

We independently extracted data from each selected report and attempted to resolve any disagreement by discussion. Where dis-agreement persisted, or if published results made data extraction difficult, we attempted to obtain clarification from the authors of the trial, pending which we assigned the trial to those awaiting assessment.

3.2 Binary outcomes

We excluded binary data if more than 50% of people were lost to follow up. Where binary outcomes (proportions) are used, we calculated relative risks (RR), fixed and 95% confidence intervals for each outcome. In addition we calculated absolute measures, the number needed to treat (NNT) and, if appropriate, the number needed to harm (NNH) with their 95% confidence intervals. We undertook analyses on an intention to treat basis.

3.3 Continuous outcomes

We excluded continuous data if more than 50% of people were lost to follow up. We reported continuous data as presented in the original studies, without making any assumptions about those lost to follow up. We calculated pooled weighted mean differences (WMD) along with confidence intervals, for outcomes using similar scales.

3.3.1 Validity of continuous measures

We only included continuous data from rating scales if the measuring instrument had been described in a peer-reviewed journal and the instrument was either a self report, or completed by an independent rater or relative (not the therapist). Unpublished instruments are more likely to report statistically significant findings than those that have been peer reviewed and published (Marshall 2000).

3.4 Leaving the study early

People dropped out of each of the studies of their own volition or as a result of a decision made by the trialists. For binary outcomes, we assigned people who left of their own accord to the least favourable outcome group. We tested the effects of this assignment in a sensitivity analysis.

3.5 Normal distribution of continuous data

Data on continuous outcomes are often not normally distributed. To avoid the pitfall of applying parametric tests to non-parametric data, all data included in the review met the following criteria:

1. standard deviations and means were reported in the paper or were obtainable from the authors;

2. when a scale started from 0 the standard deviation (SD), when multiplied by two was less than the mean (as otherwise the mean was unlikely to be an appropriate measure of the centre of the distribution (Altman 1996).

3. if a scale started from a positive value (such as PANSS that can have values from 30 to 210) the calculation described above in ii) was modified to take the scale starting point into account. In these cases skewness was considered present if 2SD>(S-Smin), where S is the mean score and Smin is the minimum score.

Data that did not meet these standards were not entered into the RevMan software (which assumes a normal distribution). However, we reported data not meeting these criteria in additional tables and in the text, if they had been analysed with appropriate non-parametric tests.

3.6 Endpoint versus change data

Where possible we presented endpoint data and if both endpoint and change data are available for the same outcomes then we only reported the former.

3.7 Cluster trials

Studies increasingly employ ‘cluster randomisation’ (such as randomisation by clinician or practice) but analysis and pooling of clustered data poses problems. Firstly, authors often fail to account for intra class correlation in clustered studies, leading to a ‘unit of analysis’ error (Divine 1992) whereby p values are spuriously low, confidence intervals unduly narrow and statistical significance overestimated. This causes type I errors (Bland 1997, Gulliford 1999).

Where clustering was not accounted for in primary studies, we presented the data in a table, with a (*) symbol to indicate the presence of a probable unit of analysis error. In subsequent versions of this review we will seek to contact first authors of studies to obtain intra class correlation co-efficients of their clustered data and to adjust for this by using accepted methods (Gulliford 1999). Where clustering has been incorporated into the analysis of primary studies, we will also present these data as if from a non-cluster randomised study, but adjusted for the clustering effect. We have sought statistical advice and have been advised that the binary data as presented in a report should be divided by a ‘design effect’. This is calculated using the mean number of participants per cluster (m) and the intra-class correlation co-efficient (ICC) Design effect = 1+(m-1)*ICC (Donner 2002). If the ICC was not reported it was assumed to be 0.1 (Ukoumunne 1999).

3.8 Presentation of data

Where possible, we entered data in such a way that the area to the left of the line of no effect indicated a favourable outcome for the intervention of interest. For some scales a high score indicates a bad outcome, but for others, high scores are good. When the latter was the case the area to the left of the line indicates a favourable outcome for the control group and is so labelled.

4. Heterogeneity

After considering the likelihood of clinical heterogeneity based on comparisons of the included studies, we visually inspected graphs to investigate the possibility of statistical heterogeneity. We calculated the value of I-squared to provide an estimate of the percentage of variability due to heterogeneity rather than chance alone. We interpreted an I-squared value of 50% or greater as indicating high levels of heterogeneity (Higgins 2003, Deeks 2004). If inconsistency was high, we did not summate data, but presented it separately and investigated the reasons for heterogeneity. In any event, if substantial heterogeneity was present, we undertook a sensitivity analysis to the presence or absence of these data.

5. Sensitivity and subgroup analysis

We undertook sensitivity analyses in all instances when heterogeneity was detected. The effect of including studies with high attrition rates was analysed in a sensitivity analysis. In addition, we detected the differences in outcomes for (a) for people with schizophrenia in whom obsessive compulsive symptoms preceded the onset of symptoms of schizophrenia, as opposed to those in whom obsessive compulsive symptoms occurred in the prodromal stages or after the symptoms of schizophrenia were established, (b) for people with schizophrenia as opposed to those with schizo-affective disorder, (c) for people with obsessive compulsive symptoms as opposed to obsessive compulsive disorder as defined by diagnostic criteria, and (d) when interventions are used in combination rather than individually.

6. Publication bias

When outcomes include data from five or more trials, we entered data into a funnel graph (trial effect versus trial size) in an attempt to investigate the likelihood of overt publication bias.

WHAT’S NEW

Date	Event	Description
27 October 2008	Amended	Converted to new review format.

HISTORY

Protocol first published: Issue 2, 2005